Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney, and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by simulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renin have been sought as agents for control of hypertension and hyperaldosteronism.
The present invention concerns novel peptides which inhibit renin. It also concerns pharmaceutical compositions containing these novel peptides, methods of treating renin-associated hypertension, congestive heart failure, glaucoma, and hyperaldosteronism, as well as the use of the peptides as diagnostic tools, and the methods for preparing the peptides.
Since HIV protease, like renin, is an aspartyl protease, these compounds can also be used to treat diseases caused by retroviruses including HTLV-I, -II, and -III.
EPA 229667 discloses certain peptidylaminodiols as renin inhibiting compounds of the formula ##STR1## wherein A is a substituent; W is C.dbd.O or CHOH, U is CH.sub.2 or NR.sub.2, provided that when W is CHOH then U is CH.sub.2 ; R.sub.1 is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxy-benzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)-methyl, (4-imidazoyl)methyl, .alpha.,.alpha.-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R.sub.2 is hydrogen or loweralkyl; R.sub.3 is loweralkyl, [(alkoxy)alkoxy]alkyl, [thioalkoxyalkyl, loweralkenyl, benzyl or heterocyclic ring substituted methyl; R.sub.4 is loweralkyl, cycloalkylmethyl or benzyl; R.sub.5 is vinyl, formyl, hydroxymethyl or hydrogen; R.sub.7 is hydrogen or loweralkyl; R.sub.8 and R.sub.9 are independently selected from OH and NH.sub.2 ; and R.sub.6 is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R.sub.5 and R.sub.7 are both hydrogen and R.sub.8 and R.sub.9 are OH, the carbon bearing R.sub.5 is of the "R" configuration and the carbon bearing R.sub.6 is of the "S" configuration, or pharmaceutically acceptable salts or esters thereof.
EPA 202577 discloses certain N-(acyldipeptidyl)-aminoglycols of formula ##STR2## wherein R.sub.1 is alkoxy containing one to six carbon atoms or lower alkyl containing one to six carbon atoms; R.sub.2 is benzyl or naphthylmethyl, R.sub.3 is lower alkyl containing one to six carbon atoms or imidazole-methyl; R.sub.4 is benzyl, R.sub.5 is hydrogen or lower alkyl, and n is 0 or 1. These compounds are useful as renin inhibitors.
The novel peptides of this invention all have an .alpha.-heteroatom amino acid at the P.sub.3 position. A designation of the various positions occupied by the amino acids is illustrated by: ##STR3## It is surprising to find such blood activity in these compounds.